Cortical Signature and Modulation of Pain Abstract/Project Summary Pain perception contains two main dimensions: the sensory-discriminative and the affective-cognitive aspects. In this proposal, we will focus on the cortical signature and modulations of the sensory aspects of pain using mouse models. Pain can be largely divided into inflammatory or neuropathic pain. A common condition in both types of pain is mechanical allodynia: externally applied innocuous gentle touch becomes painful. Paradoxically, pain elicits self-initiated recuperative behaviors such as rubbing and massaging of the painful regions; and the mechanical stimuli from such self-generated behaviors generally relieve pain. The neural circuit mechanisms underlying the opposite effects of external versus self-applied mechanical stimuli in pain conditions remain poorly understood. Based on previous research as well as our preliminary studies, we hypothesize that corticospinal projecting neurons from primary somatosensory (S1) cortex facilitate mechanical hypersensitivity in pain models, whereas specific motor cortex projection neurons play key roles in suppressing tactile allodynia in self-initiated recuperative behaviors (such as licking and wiping in mice). We further hypothesize that the cortical pain signature can be read out from activity patterns of large populations of individual S1 neurons by comparing their activities in the painful versus non-painful or pain- relieved conditions. We will use a combination of viral-genetic labeling of specific cortical neurons, in vivo calcium imaging and in vivo multi-electrode extracellular recording in freely behaving mice, optogenetics- assisted slice physiology, opto/chemicogenetic manipulations, and computational analyses to test our hypotheses.